1. Field of the Invention
The invention relates to a new class of compounds that are useful for the allosteric modification of hemoglobin. In particular the invention relates to a family of new compounds having the general structural formula set forth in FIG. 1 of the drawings. In the formula of FIG. 1, X and Z may each be CH.sub.2, NH or O.
2. The Prior Art Scenario
Hemoglobin is a tetramer with two .alpha. and two .beta. subunits. Moreover, hemoglobin is an allosteric protein in equilibrium between two allosteric structures; the deoxy or T state with low oxygen affinity and the oxy or R state with high oxygen affinity. In the past proposals have been made for attempting to influence the allosteric equilibrium of hemoglobin using synthetic compounds. These attempts have been based on the fact that high affinity hemoglobin is thought to be beneficial in resolving problems associated with the deoxy form, as in the case of sickle cell anemia. On the other hand, low affinity hemoglobin is believed to have general utility in a variety of disease states where tissues suffer from low oxygen tension, such as ischemia and cancer.
In the past, a number of chemical compounds have been identified as having utility in the allosteric regulation of hemoglobin and other proteins. For example, see Perutz, "Mechanisms of Cooperativity and Allosteric Regulation in Proteins", Quarterly Reviews of Biophysics 22, 2 (1989), pp. 163-164; and Lalezari et al., "LR16, a compound with potent effects on the oxygen affinity of hemoglobin on blood cholesterol, and on low density lipoprotein", Proc. Natl. Acad, Sci, USA 85 (1988), pp. 6117-6121. Structurally similar compounds are disclosed in German patent Publication No. 2,149,070 but without any indication of a potential for allosteric hemoglobin modification. As in other related fields the search continues for drugs that can be conveniently prepared and which provide optimum therapeutic results.